The majority of eucaryotic and viral small nuclear and messenger RNAs, analyzed to date, have a unique chemical structure at their 5' terminus which is required in varying degrees for their maturation, stability, and efficacy in translation. We propose to determine if the removal or alteration or alteration of the 5' CAP of messenger RNA by a reactive moiety coupled to an antisense oligonucleotide is a viable approach for the regulation of gene expression. We propose to first screen for reactive functional groups which catalytically cleave the phosphoanhybride, phosphomonoester anhydride, or N-glycosidic bond to result in the removal of the 5' CAP under physiological conditions. Reactive groups from this screening process will then be tethered to an appropriate antisense oligonucleotide. Molecular mechanics and modeling using computer graphics software packages will be used to assist in the design of the antisense hybrid, such as in the tether length and composition. Cleavage assays will be done by chromatography (TLC, paper electrophoresis, and HPLC) using capped monoribonucleotides as substrate.